EP1692105A1 - Method for producing (3-oxo-2,3-dihydro-1h-isoindol-1-yl) acetylguanidine derivatives - Google Patents

Abstract

The invention relates to methods for producing (3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetylguanidine derivatives of formula (I) using 3-hydroxy-2,3-dihydro-1 H-isoindol-1-one derivatives or 3-(2-carbamoyl-phenyl) acrylic acid ester derivatives as intermediate stages, to a method for the resolution of racemates and to intermediate products of the inventive method.

Description

Process for the preparation of (3-oxo-2,3-dihydro-H-isoindol-1-yl) -acetylguanidine derivatives

The present invention relates to processes for the preparation of (3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetylguanidine derivatives via 3-hydroxy-2,3-dihydro-1H-isoindole-1 ■ on-derivatives or 3- (2-carbamoyl-phenyl) -acrylic acid ester derivatives as intermediates, a process for the resolution of racemates, as well as intermediates of the inventive method.

(3-0x0-2, 3-dihydro-1H-isoindol-1-yl) -acetylguanidine derivatives of the formula I.

are NHE1 inhibitors and are described in PCT / EP03 / 05279. However, the syntheses described therein lead to racemic regioisomer mixtures, which requires complicated separation processes and reduces the yield of the desired compound. Until now, access to the enantiomers was only possible by means of a complicated chromatographic separation on chiral supports. However, the substance throughput in chromatographic separations is limited.

There has therefore been great interest in regioselective preparation processes for (3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetylguanidine derivatives and processes for

To find recovery of the enantiomers. The improved, regioselective preparation of the racemic (3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetylguanidine derivatives was achieved in two independent ways, shown in Scheme 1 and Scheme 3. The cleavage of the racemates was achieved by crystallization as salts of 2,3-O-acylated D- or L-tartaric acids, as shown in Scheme 5. By careful base-catalyzed racemization of the respective undesired enantiomer, a substantial conversion of the racemate into the desired enantiomer is possible. The mentioned Methods allow the simple preparation of enantiomerically enriched or enantiomerically pure (3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetylguanidine derivatives. The novel process now makes it possible to produce large quantities of the compounds of the formula I on an industrial scale in a simple manner.

The present invention thus relates to a process for the preparation of

Compounds of the formula I,

wherein R 1 and R 2 independently of one another denote hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 C atoms; R3 is alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 C atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; and their salts; characterized in that as shown in Scheme 1

VII

Scheme 1

a) the amide of the formula IV is formylated and then cyclized to the compound of the formula VI, b) the compound of the formula VI is reacted with an alkoxycarbonylmethylenetriphenylphosphorane, with a 1-alkoxy-1-trimethylsiloxyethylene or with a trialkylphosphonoacetate to give the compound of the formula VII and c) the compound of the formula VII is reacted with guanidine to give the compound of the formula I, where in the compounds of the formulas IV, VI and VII

R1 to R3 are defined as in formula I and

R5 is alkoxy having 1, 2, 3 or 4 carbon atoms; and their salts.

The invention also provides a process for the preparation of compounds of the formula I, where

R 1 and R 2 independently of one another are hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 C atoms;

R3 is alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 C atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; and their salts; characterized in that as shown in Scheme 2

VII

Scheme 2

a) the compound of the formula II is reacted with the amine of the formula III to form the amide of the formula IV, b) the amide of the formula IV is formylated at the ortho position to the amide function to give the formylamide of the formula V, c) the formyl amid of formula V is cyclized to the compound of formula VI, d) the compound of formula VI with an alkoxycarbonylmethylenetriphenyl phosphorane, with a 1-alkoxy-1-trimethylsiloxyethylen or with a

Trialkylphosphonoacetat is converted to the compound of formula VII and e) the compound of formula VII is reacted with guanidine to the compound of formula I, wherein in the compounds of formulas II, III, IV, V, VI and VII R1 to R3 are defined as in formula I, R5 is alkoxy having 1, 2, 3 or 4 C atoms and X is Cl, Br, OH or alkoxy having 1, 2, 3 or 4 C atoms; and their salts.

The compound of formula II is usually in an inert solvent such as an ether, hydrocarbon or halogenated hydrocarbon, for example dichloromethane, at a temperature between -30 ° C and the boiling point of the solvent, preferably at RT, with an amine of formula III, optionally in the presence of an activating agent, converted to the amide of formula IV.

The ortho-formylation can be carried out, for example, by adding an alkyl metal compound, for example an alkyllithium compound, preferably t-BuLi, with a complexing ligand, preferably TMEDA, in an inert solvent such as an ether or hydrocarbon, for example THF a temperature between -100 ° C and 0 ° C, preferably between -80 ° C and -50 ° C, is presented. Then the amide of formula IV is added and over a period between 10 minutes and 10 hours, preferably between 10 minutes and 60 minutes, at a temperature between -100 ° C and 0 ° C, preferably between -80 ° C and -50 ° C, deprotonated. Subsequently, a formylating agent, preferably DMF, is added and reacted with the anion at a temperature between -100 ° C and 40 ° C, preferably between -80 ° C and room temperature. Preferably, the solution is allowed to come to RT after addition of the DMF for a period of 10 minutes to 3 hours, for example within 30 minutes. Intermediate amide of formula V cyclized thereby generally directly to the isoindolone of the formula VI.

The isoindolone of the formula VI is reacted with a (C 1 -C 4) -alkoxycarbonylmethylenetriphenylphosphorane in an inert solvent such as an ether, hydrocarbon or halogenated hydrocarbon, for example toluene, at a temperature between 0 ° C. and the boiling point of the solvent, preferably between 20 ° C and the boiling point of the solvent, or with a tri- (C- | -C4) - Alkylphosphonacetat in the presence of a base, for example sodium hydride, in an inert solvent such as an ether, hydrocarbon or halogenated hydrocarbon, for example 1, 2-dimethoxyethane, at a temperature between 0 ° C and the boiling point of the solvent, preferably between 20 ° C and the boiling point of the solvent reacted. Alternatively, the isoindolone of the formula VI is reacted with a 1- (C 1 -C 4) -alkyloxy-1-trimethylsiloxyethylene in the presence of a

Lewis acid, for example titanium (IV) chloride or trimethylsilyl triflate, in an inert solvent such as an ether, hydrocarbon or halogenated hydrocarbon, for example dichloromethane, at a temperature between -80 ° C and the boiling point of the solvent, preferably at a temperature between -80 ° C and 20 ° C, reacted (Synth Commun., 1987, 17, 1).

The ester of formula VII can be reacted with guanidine to the acylguanidine of formula I by well known methods. The reaction is preferably carried out in a manner known to those skilled in a protic or aprotic, polar, but inert organic solvent. For example, in the reaction of the methyl ester (formula VII; R5 = OCH3) with guanidine, solvents such as

Methanol, isopropanol or THF at temperatures of 20 ° C to the boiling point of these solvents proven. Most reactions of compounds of formula VII with salt-free guanidine, for example, in aprotic inert solvents, for example, ethers such as THF, dimethoxyethane or dioxane worked. But also water can be used with the use of a base such as NaOH as a solvent in the reaction of compounds of formula VII with guanidine. In the reaction of compounds of the formula VII with salts of guanidine, for example guanidine hydrochloride, the reaction is usually carried out in the presence of a base, for example potassium tert-butoxide, sodium methoxide or sodium ethylate in an inert solvent, such as dimethylformamide, NMP, 2-propanol at a temperature between 20 ° C and the boiling point of the solvent.

In addition to the carboxylic acid esters of the formula VII, it is also possible to use further activated acid derivatives in the reaction with guanidine, for example Carboxylic acid chlorides, thioesters or anhydrides. There may also be an activation of the carboxylic acid with, for example, DCC. The activated acid derivatives can be prepared in a manner known to those skilled in the art directly from the underlying carboxylic acid esters of the formula VII or from the corresponding carboxylic acids which can be obtained from the esters by conventional hydrolysis methods. A number of suitable methods for the preparation of activated carboxylic acid derivatives are given with reference to source literature in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985, p. 350).

The process steps described in Scheme 1 and 2 can be carried out independently of one another continuously or discontinuously. A work-up of the reaction mixture can be carried out after each of the process steps. The workup and, if desired, the purification of the products is carried out by the customary methods such as extraction, pH separation, chromatography or crystallization and the usual drying.

The starting compounds of the formulas II and III are commercially available or can be prepared by or analogously to processes described in the literature and known to the person skilled in the art.

Also claimed is a process for the preparation of compounds of the formula

wherein R 1 and R 2 independently of one another denote hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 C atoms; R3 is alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 C atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; and their salts; characterized in that as shown in Scheme 3

IX XI Scheme 3

a) the amine of formula IX is reacted with a diazonium salt with an acrylic acid alkyl ester to Zimtsäurederivat of formula XI, b) the compound of formula XI is reacted with the amine of formula III and with guanidine to the acylguanidine of formula I, wherein in the Compounds of formulas III, IX and XI R1 to R3 are defined as in formula I and R6 is alkoxy having 1, 2, 3 or 4 C atoms; and their salts.

The present invention also relates to a process for the preparation of the compounds of the formula I,

wherein R 1 and R 2 independently of one another denote hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 C atoms;

R3 is alk-R4 or trifluoromethyl; ^• Alk is alkyl having 1, 2, 3 or 4 carbon atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; and their salts; characterized in that as shown in Scheme 4

Scheme 4

a) the nitro compound of the formula VIII is converted to the amine of the formula IX, b) the amine of the formula IX is converted to the diazonium salt of the formula X, c) the diazonium salt of the formula X is reacted with an acrylic acid alkyl ester to give the cinnamic acid derivative of the formula d) the compound of formula XI is converted to the amide of formula XII and e) the compound of formula XII is converted to the acylguanidine of formula I, either by reacting the compound of formula XII in the presence of a base to the isoindolone derivative of formula XIII and then by reaction with guanidine to activate the acylguanidine of formula I (alternative A), or after formation of the isoindolone derivative of formula XIII in the presence of a base of the compound of formula XII by converting the compound of formula XIII into the ester of formula XIV and then by reaction with guanidine to the acylguanidine of formula I (alternative B), or by reacting the compound of formula XII in Gegenw a strong base to the ester of formula XIV and then by reaction with guanidine to the acylguanidine of formula I (alternative C), or by direct reaction of the compound of formula XII with guanidine in the presence of a base with simultaneous guanylation and cyclization to the isoindolone of the formula I (alternative D), wherein in the compounds of formulas VIII, IX, X, XI, XII, XIII and XIV R1 to R3 are defined as in formula I and R6 and R7 are independently alkoxy with 1, 2, 3 or 4 C Atoms are; and their salts.

The nitro compound of the formula VIII can be prepared by known methods (for example described in "Houben-Weyl, Methods of Organic Chemistry", Volume XI / 1, nitrogen compounds II, Georg Thieme Verlag Stuttgart, 1957, p 360ff) to the aniline of the formula IX Preference is given to catalytic hydrogenation, for

Example with Pd / C, for example with 5% Pd / C or 10% Pd / C, in a solvent such as an alcohol, preferably ethanol, under a hydrogen atmosphere of-1 bar to 200 bar pressure, preferably 1 bar to 10 bar pressure.

The subsequent diazotization of the aniline of the formula IX is carried out in an inert solvent, preferably ethanol, in the presence of an acid whose anion does not itself replace the diazonium ion, such as HBF4 or HPFρ, preferably HBF4, or to Example H2SO4 and. in the presence of a nitrite, preferably NaNO 2, at one

Temperature between -30 ° C and the boiling point of the solvent, preferably between 0 ° C to 30 ° C.

The diazonium salt of the formula X is preferably reacted directly with an acrylic acid (C 1 -C 4) -alkyl ester, preferably ethyl acrylate, in the presence of a

Palladium catalyst, preferably Pd (OAc) 2, at a temperature between 0 ° C and the boiling point of the solvent, preferably between 45 ° C to 55 ° C, to Zimtsäurederivat of formula XI.

The benzoic acid function of the compound of the formula XI can be converted into the amide of the formula XII by methods known to the person skilled in the art, preferably via the acid chloride or with the aid of DCC. This reaction can also be carried out so that the amide of the formula XII is cyclized in the reaction mixture directly to the ester of formula XIV, that is, the reaction of the compound of formula XI to ester of formula XIV is carried out in one step. This can be done either schoη under the basic reaction conditions of amide formation, or the cyclization can be effected by the addition of a base such as triethylamine, Hünig base or potassium tertiary butylate. Another alternative is to directly convert the compound of formula XI to the compound of formula I by sequentially carrying out amide formation, cyclization and guanidation in the same reaction vessel, which reaction can be carried out without isolation of intermediates.

For the further reaction of the compound of formula XII to the acylguanidine of formula I, there are 4 alternatives: Alternative A: The reaction of the amide of the formula XII is preferably carried out with aqueous alkali solution, preferably aqueous NaOH solution, in a solvent such as an alcohol, preferably methanol or ethanol, at a temperature between -30 ° C and the boiling point of the solvent, preferably at RT. Both saponification of the ester function and cyclization to the isoindolone derivative of formula XIII take place. The compound of formula XIII is described (and as to Scheme 1) by generally known methods is activated for acylation, for example via the acid chloride or with DCC, and the acylguanidine of the formula is obtained \ ^".

Alternative B: As in alternative A, the synthesis of the carboxylic acid of the formula XIII takes place. Subsequently, using standard procedures for ester production, preferably with SOCl 2 in an alcohol such as methanol or ethanol, for example, the methyl or ethyl ester of formula XIV. The subsequent reaction of the ester of the formula XIV is carried out as described for Scheme 1 to the acylguanidine of the formula I.

Alternative C: The reaction of the amide of the formula XII is carried out in a solution of a strong base, preferably methylate or t-butylate in an alcohol such as methanol or ethanol, to give the methyl or ethyl ester of the formula XIV. The reaction of the ester of Formula XIV to the acylguanidine of formula I is carried out as described for Scheme 1.

Alternative D: The amide of formula XII is reacted under usual conditions for the acylation of guanidine. The solvent used is an inert solvent such as an ether, hydrocarbon or halogenated hydrocarbon, preferably DMF. Usually, a guanidinium salt is first reacted with a strong base, preferably KOtBu, whereby the free guanidine is liberated. The mixture is added to the solution of the compound of formula XII in a solvent such as an alcohol, ether, hydrocarbon or halogenated hydrocarbon, for example DMF, NMP or 2-propanol. At the same time, the guanylation and the cyclization to the isoindolone of formula I occur. A variant consists in chronological succession with a catalytic amount of a strong base, for example, potassium tert-butylate or sodium methoxide or sodium in a solvent, for example DMF, NMP or 2-propanol, to cyclize the compound of formula XI to the compound of formula XIV and then react in situ to give the compound of formula I.

Alternative D is preferred in which the reaction of the benzoic acid derivative of the formula XI in a one-pot process is carried out as far as the acylguanidine of the formula I.

The process steps described in Scheme 2 can be carried out continuously or batchwise. A work-up of the reaction mixture can be carried out after each of the process steps. The workup and, if desired, the purification of the products is carried out by the customary methods such as extraction, pH separation, chromatography or crystallization and the usual drying.

The starting compounds of the formulas III and VIII are commercially available or can be prepared by or analogously to processes described in the literature and known to the person skilled in the art.

The invention also relates to compounds of the formula XII

wherein R 1 and R 2 independently of one another denote hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 C atoms; R3 is alk-R4 or trifluoromethyl; Alk alkyl having 1, 2, 3 or 4 C atoms ^" ; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; R6 alkoxy having 1, 2, 3 or 4 carbon atoms; and their salts.

Claimed is also the use of the compounds of formula XII as a synthesis intermediate.

Compounds of the formula I in enantiomerically enriched or enantiomerically pure form can advantageously be prepared by a novel resolution process, which is also the subject of the present invention. For this purpose, the racemates of the compounds of the formula I are crystallized as salts of 2,3-O-acylated D- or L-tartaric acids, wherein the enantiomers accumulate in the crystallizate or in the mother liquor. Subsequently, the free bases are released again from the salts.

The present invention thus relates to a process for the isolation of the compounds of formula Ia and Ib

where mean

R 1 and R 2 independently of one another are hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 C atoms;

R3 is alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 C atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; and their salts; characterized in that as shown in Scheme 5

la Ib Scheme 5

a) reacting the compound of the formula I to salts of a 2,3-O-acylated D- or L-tartaric acid and, by crystallization, the two salts of the formulas XVa and XVb are obtained separately, and b) the free bases of the formulas Ia or Ib are liberated from the two salts of the formulas XVa or XVb, where in the compounds of the formulas I, XVa and XVb R1 to R3 are defined as in the formulas Ia and Ib and R *

means and

R 8 is alkyl having 1, 2, 3, 4, 5 or 6 C atoms or phenyl which is unsubstituted or substituted by 1, 2 or 3 substituents from the group F, Cl, Br, I, alkyl having 1, 2, 3 or 4 C atoms or alkoxy having 1, 2, 3 or 4 C atoms.

It also claims the method described above, in which the undesired enantiomer of the formula Ia or Ib is racemized again.

The racemate of the compound of the formula I is reacted with a tartaric acid derivative R *, for example O, O'-dibenzoyl-D-tartaric acid, O, O'-dibenzoyl-L-tartaric acid, O, O-di (4-methylbenzoyl) - L-tartaric acid, O, O'-di (4-methylbenzoyl) -D-tartaric acid, O, O-di (4-methoxybenzoyl) -L-tartaric acid or O, O'-di (4-methoxybenzoyl) -D- Tartaric acid, preferably with O, O'-dibenzoyl-L-tartaric acid or O, O'-dibenzoyl-D-tartaric acid, crystallized in a suitable solvent such as an ether, for example diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran or dioxane in a halogenated hydrocarbon, for example dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane or trichlorethylene, in an alcohol, for example methanol, ethanol, n-propanol, 2-propanol, butanol, in an ester, for example ethyl acetate or Butyl acetate, in water, or in mixtures of solvents, preferably in 2-propanol, dimethoxyethane or ethyl acetate, at a temperature between -10 ° C and the boiling point of the solvent, preferably at 0 ° C to 40 ° C. A variant of the method consists in using mixtures of two or more 2,3-O-acylated D- or L-tartaric acids of the same configuration, which carry different acyl groups, for the separation.

The salt formation from the compound of the formula I and the tartaric acid derivative R * can be carried out using equivalent amounts, ie 0.5 mol of the tartaric acid derivative R * containing two carboxylic acid groups can be used per mole of the compound of the formula I. However, the compound of the formula I can also be crystallized with less than 0.5 molar equivalents of 2,3-O-acylated D- or L-tartaric acid, for example with 0.25 mol to 0.5 mol of tartaric acid derivative R * per mole of the compound of the formula I, in particular with 0.25 mol to 0.3 moles of tartaric acid derivative R * per mole of the compound of formula I. The desired enantiomer then crystallizes out in the form of the salt of formula XVa or XVb and the undesired enantiomer is in the mother liquor for the most part in the form of the enantiomer of formula Ib or la and not in the form of the salt of the formula XVa or XVb included. The enantiomeric purity of the salts of formulas XVa and XVb can be increased by repeated crystallization or by stirring the primary crystals with fresh solvent at elevated temperature and subsequent cooling. After separation of the two salts of the formulas XVa and XVb or separation of the salt of the formula XVa or XVb from the undesired enantiomer Ib or la, the enantiomerically enriched compounds of the formulas Ia and Ib are then usually added by addition of an auxiliary base, for example an amine such as Example triethylamine, an inorganic base such as NaHC0 ₃ , Na ₂ C0 ₃ or their aqueous solutions, released from the salts. It is usually carried out in a suitable solvent such as in an ether, for example diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran or dioxane, in a halogenated hydrocarbon, for example dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane or trichlorethylene, in an alcohol , For example, methanol, ethanol, n-propanol, 2-propanol or butanol, in an ester, for example ethyl acetate or butyl acetate, or in water or in solvent mixtures, preferably in ethyl acetate, 2-propanol, dichloromethane or water or mixtures thereof, wherein the reaction mixture may have one or more phases, at a temperature between -10 ° C and the boiling point of the solvent, preferably at 10 ° C to 40 ° C. This can be so for example

- That the salt is dissolved in aqueous NaHCO 3 solution and then extracted with an organic solvent, for example ethyl acetate, the enantiomer of formula Ia or Ib. The respectively undesired enantiomer Ia or Ib can be converted back into the racemate of the formula I by a racemization process and is thus available for a further resolution of the racemate. The undesired enantiomers here are preferably used in a solvent such as an alcohol, for example 2-propanol, at a temperature between -10 ° C and the boiling point of the solvent, preferably at 0 ° C to 40 ° C, with small amounts of a base, for example KOH, treated, neutralized the reaction mixture and isolated after aqueous-extractive work-up, the racemate. This process can be carried out by appropriate choice of the amount of base and reaction temperature so that virtually exclusively racemization and no chemical change of the substance occurs.

The present invention furthermore relates to compounds of the formulas XVa and XVb

wherein R 1 and R 2 independently of one another denote hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 C atoms; R3 is alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 C atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; ^' '

R *

R 8 is alkyl having 1, 2, 3, 4, 5 or 6 C atoms or phenyl which is unsubstituted or substituted by 1, 2 or 3 substituents from the group F, Cl, Br, I, alkyl having 1, 2, 3 or 4 C atoms or alkoxy having 1, 2, 3 or 4 C atoms.

If the compounds described above, for example the compounds of the formulas I, Ia, Ib, VII, XIII, XIV, XVa or XVb, contain one or more asymmetric centers, these may independently of one another be configured both as S and R, unless otherwise stated specified. The compounds may exist as optical isomers, as diastereomers, as racemates or as mixtures thereof, unless otherwise specified. Double bonds can be both the E and the Z configuration, unless stated otherwise. The present invention includes all tautomeric forms of the compounds described above, for example the compounds of formulas I, Ia, Ib, XVa and XVb.

Alkyl radicals can be straight-chain or branched. This also applies if they carry substituents or occur as substituents of other radicals, for example in fluoroalkyl radicals or alkoxy radicals. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl (= 1-methylethyl), n-butyl, isobutyl (= 2-methylpropyl), sec-butyl (= 1-methylpropyl), tert-butyl (= 1, 1 -Dimethylethyl), n-pentyl, isopentyl, tert-pentyl, neopentyl and hexyl. Preferred alkyl radicals are methyl, ethyl, n-propyl and isopropyl, particularly preferably methyl or ethyl. In alkyl radicals, one or more, for example 1, 2, 3, 4 or 5, hydrogen atoms may be substituted by fluorine atoms. Examples of such fluoroalkyl radicals are trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl, preferably trifluoromethyl or 2,2,2-trifluoroethyl. Substituted alkyl radicals may be substituted in any positions. Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Pheriyl radicals can be unsubstituted or monosubstituted or polysubstituted, for example monosubstituted, disubstituted or trisubstituted, by identical or different radicals. When a phenyl radical is substituted, it preferably carries one or two identical or different substituents. In monosubstituted phenyl radicals, the substituent may be in the 2-position, the 3-position or the 4-position. Double substituted phenyl may be substituted in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisubstituted phenyl radicals, the substituents can be in the 2,3,4-position, 2,3,5-position, 2,4,5-position, 2,4,6-position, 2,3,6-position or 3 , 4,5 position.

The compounds described above, for example the compounds of the formulas I, Ia and Ib, can be used in the form of their salts in the processes according to the invention and / or isolated in the form of their salts. Salts can be obtained by the usual methods, for example, by reaction with acids or bases in a solvent or by anion exchange or cation exchange from other salts. Examples of acid addition salts, for example of the compounds of the formulas I, Ia and Ib, are halides, in particular hydrochlorides, hydrobromides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, benzenesulfonates, p-toluenesulfonates, adipinates, fumarates, gluconates, Glutamates, Glycerolphosphäte, maleinates, benzoates, oxalates and pamoates and trifluoroacetates in question. In the case of the preparation of active ingredients, physiologically acceptable salts and pharmaceutically acceptable salts are preferred. Examples ^■ salts of compounds of formulas I, la and Ib with fumaric acid may be mentioned, in particular salts containing one mole of fumaric acid per mole of the compound of formula I, Ia or Ib, and which are thus Hydrogenfumarate or Hemifumarate. By advantageous properties such as crystallinity, stability, a particularly low hygroscopicity, a low tendency to racemization and good solubility is specifically characterized, for example, the (S) -N- {2- [3-oxo-2- (2,2,2-trifluoroethyl ) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] -acetyl} -guanidine Hydrogen fumarate hydrate of the formula XVI, which is also the subject of the present invention in all its tautomeric forms.

When the compounds contain an acid group, they may form salts with bases, for example, alkali metal salts, preferably sodium salts or potassium salts, or ammonium salts, for example, salts with ammonia or organic amines or amino acids. Compounds containing a basic group and an acid group may also exist as zwitterion.

One embodiment of the present invention relates to compounds in which R1 and R2 are not both hydrogen, in particular compounds in which R1 is hydrogen and R2 is fluorine, chlorine or trifluoromethyl, especially trifluoromethyl. In compounds where R1 is hydrogen, the substituent R2 is preferably in the para position of the benzene ring relative to the C = O group in the isoindolone system.

The group Alk preferably represents alkyl having 1, 2 or 3 C atoms, in particular having 1 or 2 C atoms, especially with 1 C atom. R 4 is preferably trifluoromethyl or cycloalkyl having 3, 5 or 6 C atoms, in particular 3 C atoms, particularly preferably trifluoromethyl. One embodiment of the present invention relates to compounds in which R 3 is trifluoromethyl or 2,2,2-trifluoroethyl, in particular 2,2,2-trifluoroethyl.

A specific embodiment of the present invention relates to the preparation of N- {2- [3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl ] -acetyl} guanidine and its enantiomeric forms and salts thereof. X is preferably chlorine or methoxy, in particular chlorine. R 5 is preferably methoxy or ethoxy, in particular ethoxy. ^' R6 is preferably methoxy or ethoxy, in particular ethoxy. R 7 is preferably methoxy or ethoxy, in particular ethoxy.

In one embodiment of the present invention R 8 is phenyl which is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group F, Cl, alkyl having 1, 2, 3 or 4 C atoms or alkoxy having 1, 2, 3 or 4 C atoms, in particular unsubstituted phenyl.

The compounds of the formulas I, Ia, Ib, XVa and XVb and their pharmaceutically acceptable salts are substituted acylguanidines and inhibit the cellular

Sodium proton antiporter (Na ⁺ / H ⁺ exchanger, NHE), in particular the subtype NHE-1.

Due to the NHE-inhibitory properties, the compounds of the formulas I, Ia, Ib, XVa, XVb and XVI and / or their pharmaceutically acceptable salts are suitable for the prevention and treatment of diseases which are caused by an activation or by an activated NHE, and diseases secondary to the NHE-related damage.

The compounds of the formula I, Ia, Ib, XVa and XVb can also be used for the treatment and prevention of diseases, wherein the NHE is only partially inhibited, for example by using a lower dosage.

Since NHE inhibitors predominantly act by influencing cellular pH regulation, they can generally be favorably combined with other intracellular pH regulating compounds, with inhibitors of the carbonic anhydrase enzyme group inhibiting bicarbonate ion transporting systems such as the Sodium bicarbonate cotransporters (NBC) or the sodium-dependent chloride bicarbonate exchanger (NCBE), as well as NHE inhibitors with an inhibitory effect on other NHE subtypes, may be considered as combination partners, because through them the pharmacologically relevant pH-regulating effects of the NHE inhibitors described here can be enhanced or modulated.

The use of the compounds of the formulas I, Ia, Ib, XVa, XVb or XVI relates to the prevention and treatment of acute and chronic diseases in veterinary and human medicine. Thus, the inhibitors of NHE according to the invention are suitable for the treatment of diseases caused by ischaemia and by reperfusion.

The compounds described here are due to their pharmacological

Properties suitable as antiarrhythmic drugs. By their cardioprotective component NHE inhibitors are ideal for infarction prophylaxis and infarction treatment and for the treatment of angina pectoris, while they preventively prevent or greatly reduce the pathophysiological processes in the development of ischemic-induced damage, especially in the induction of ischemic induced cardiac arrhythmias. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds according to the invention of the formulas I, Ia, Ib, XVa, XVb and XVI and / or their pharmaceutically acceptable salts can be used as a medicament for treatment as a result of inhibition of the cellular Na ⁺ / H ⁺ exchange mechanism all acute or chronic ischemia-induced damage, or primary or secondary induced disease.

This also applies to their use as drugs for surgical procedures. Thus, the compounds can be used in organ transplants, the compounds both for the protection of organs in the donor before and during removal, for the protection of organs removed, for example, during treatment with or storage in physiological bath fluids, as well as in the transfer to the Recipient organism can be used. The compounds according to the invention are likewise valuable, protective drugs in the performance of angioplastic surgical procedures, for example, on the heart as well as on peripheral organs and vessels.

Furthermore, the compounds according to the invention can be used in carrying out bypass operations, for example in coronary artery bypass grafting and in Coronary Artery Bypass Graft (CABG).

In accordance with their action against ischemic-induced damage, the compounds of the formula I according to the invention can also be used for resuscitation after a cardiac arrest.

The compounds of the invention are of interest for drugs against life-threatening arrhythmias. Ventricular fibrillation is stopped and the physiological sinus rhythm of the heart is restored.

Because NHE1 inhibitors protect human tissue and organs, particularly the heart, not only effectively against damage caused by ischemia and reperfusion, but also against the cytotoxic effects of drugs, particularly those used in cancer therapy and the therapy of

Autoimmune diseases apply, the combined administration with NHE inhibitors is suitable to inhibit the cytotoxic, especially cardiotoxic side effects of said compounds. In addition, by reducing cytotoxic effects, particularly cardiotoxicity, due to co-medication with NHE1 inhibitors, the dose of cytotoxic therapeutics may be increased and / or prolonged medication with such drugs. The therapeutic benefit of such cytotoxic therapy can be significantly increased by the combination with NHE inhibitors.

In addition, NHE1 inhibitors may be used in cardiovascular overproduction of thyroid hormones, thyrotoxicosis, or in the external delivery of thyroid hormones. The compounds of the formulas I, Ia, Ib, XVa, XVb and XVI and / or their pharmaceutically acceptable salts are thus suitable for improving the therapy with cardiotoxic medicaments.

In accordance with their protective action against ischemic-induced damage, the compounds of the invention are also useful as medicaments for the treatment of

Ischemias of the nervous system, in particular the central nervous system, being suitable, for example, for the treatment of stroke or brain edema.

NHE inhibitors are also useful in the therapy and prophylaxis of diseases and disorders caused by over-excitability of the central nervous system, in particular for the treatment of epileptic disorders, centrally triggered clonic and tonic spasms, mental depression, anxiety disorders and psychosis. The NHE inhibitors described here can be used alone or in combination with other antiepileptic substances or antipsychotic agents, or carbonic anhydrase inhibitors, for example with acetazolamide, and with other inhibitors of NHE or the sodium-dependent chloride bicarbonate exchanger (NCBE).

In addition, NHE inhibitors are also useful in the treatment of forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

The compounds of the formulas I, Ia, Ib, XVa, XVb and XVI and / or their pharmaceutically acceptable salts can likewise be used for the prevention and for the treatment of thrombotic disorders since, as NHE inhibitors, they themselves can inhibit platelet aggregation. In addition, they can inhibit or prevent the excessive release of inflammatory and coagulation mediators, especially von Willebrand factor and thrombogenic selectin proteins, which takes place after ischemia and reperfusion. Thus, the pathogenic effect of significant thrombogenic factors can be reduced and turned off. Therefore, the NHE inhibitors of the present invention are combinable with other anticoagulant and / or thrombolytic agents such as recombinant or natural tissue plasminogen activator, streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factor Xa antagonists, fibrinolytic drugs, thromboxane receptor antagonists, phosphodiesterase Inhibitors, Factor VIIa antagonists, clopidogrel, ticolopidine, etc. A combined use of the subject NHE inhibitors with NCBE inhibitors and / or with carbonic anhydrase inhibitors, such as with acetazolamide, is particularly beneficial.

In addition, NHE inhibitors are characterized by potent inhibitory activity on cell proliferation, such as fibroblast cell proliferation and vascular smooth muscle cell proliferation. Therefore, the compounds of formulas I, Ia, Ib, XVa, XVb and XVI and / or their pharmaceutically acceptable salts are useful as therapeutically useful agents for diseases in which proliferation is a primary or secondary cause and may therefore be used as antiatherosclerotic agents against chronic renal failure, cancers, can be used.

It has been shown that NHE inhibitors inhibit cell migration. Therefore, the compounds of the formulas I, Ia, Ib, XVa, XVb and XVI and / or their pharmaceutically acceptable salts are useful as therapeutics for diseases in which cell migration is a primary or secondary cause, such as cancer with a pronounced tendency to Metastasis.

NHE inhibitors are further characterized by a delay or prevention of fibrotic diseases. They are thus useful as excellent agents for the treatment of fibrosis of the heart, as well as lung fibrosis, liver fibrosis, renal fibrosis and other fibrotic disorders. They can thus be used for the treatment of organ hypertrophy and hyperplasia, for example of the heart and the prostate. They are therefore for the prevention and treatment of heart failure (congestive heart failure = CHF) as well as in the Treatment and prevention of prostate hyperplasia or prostatic hypertrophy suitable.

Since NHE is significantly increased in essential hypertensives, the compounds of the formulas I, Ia, Ib, XVa, XVb and XVI and / or their pharmaceutically acceptable salts are suitable for the prevention and treatment of hypertension and for the treatment of cardiovascular diseases. They can be used alone or with a suitable combination and formulation partner for hypertension treatment and cardiovascular diseases. For example, one or more thiazide-type diuretics, loop diuretics, aldosterone and pseudoaldosterone antagonists such as hydrochlorothiazide, indapamide, polythiazide, furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene, spironolactone or Epleron can be combined. Further, the NHE inhibitors of the present invention may be used in combination with calcium antagonists such as verapamil, diltiazem, amiodipine or nifedipine, as well as with ACE inhibitors such as ramipril, enalapril, lisinopril, fosinopril or captopril. Further favorable combination partners are also β-blockers such as metoprolol, albuterol etc., antagonists of the angiotensin receptor and its receptor subtypes such as losartan, irbesartan, valsartan, omapatrilat, gemopatrilat, endotlielin antagonists, renin inhibitors, adenosine receptor agonists, inhibitors and Activators of

Potassium channels such as glibenclamide, glimepiride, diazoxide, cromakalim, minoxidil and their derivatives, activators of the mitochondrial ATP-sensitive potassium channel (mitoK (ATP) channel), inhibitors of Kv1.5, etc.

It was found that NHE1 inhibitors have a significant anti-inflammatory effect and can thus be used as anti-inflammatory agents. In this case, the inhibition of the release of inflammatory mediators falls on. The compounds can thus be used alone or in combination with an anti-inflammatory drug in the prevention or treatment of chronic and acute inflammatory diseases. As a combination partner, steroidal and non-steroidal anti-inflammatory agents are advantageously used. Furthermore, the compounds of the invention for the prevention or treatment of diseases caused by protozoa, such as malaria and chickencoccidiosis.

It has also been found that NHE inhibitors show a favorable effect on the serum lipoproteins. It is generally accepted that high levels of blood lipid levels, so-called hyperlipoproteinemias, are a major risk factor for the development of arteriosclerotic vascular changes, especially coronary heart disease. For the prophylaxis and regression of atherosclerotic changes, therefore, the reduction of elevated serum lipoproteins is of extraordinary importance. In addition to the reduction of serum total cholesterol, the reduction of the proportion of specific atherogenic lipid fractions of this total cholesterol, in particular of the low-density lipoproteins (LDL) and the very low-density lipoproteins (VLDL), is of particular importance, since these lipid fractions represent an atherogenic risk factor. In contrast, high-density lipoproteins are considered to have a protective function against coronary heart disease. Accordingly, hypolipidemic agents should be able to lower not only total cholesterol, but in particular VLDL and LDL serum cholesterol fractions. It has now been found that NHE1 inhibitors show valuable therapeutically utilizable properties with regard to influencing serum lipid levels. Thus, they significantly lower the elevated serum concentrations of LDL and VLDL, as can be observed, for example, by increased dietary intake of a cholesterol-rich and lipid-rich diet or in pathological metabolic changes, for example genetically determined hyperlipidemias. They can therefore be used for the prophylaxis and regression of atherosclerotic changes by eliminating a causal risk factor. These include not only the primary hyperlipidemia, but also certain secondary hyperlipidaemias, such as occur in diabetes, for example. In addition, NHE inhibitors lead to a marked reduction in metabolic abnormalities induced infarcts and in particular to a significant reduction in the induced infarct size and its severity. The compounds of the formulas I, Ia, Ib, XVa, XVb and XVI according to the invention therefore find advantageous use for the preparation of a medicament for the treatment of hypercholesterolemia; for the manufacture of a medicament for the prevention of atherogenesis; for the manufacture of a medicament for the prevention and treatment of atherosclerosis, for the manufacture of a medicament for the prevention and treatment of diseases caused by elevated cholesterol levels, for the manufacture of a medicament for the prevention and treatment of diseases caused by endothelial dysfunction for the manufacture of a A medicament for the prevention and treatment of atherosclerosis-induced hypertension, for the manufacture of a medicament for the prevention and treatment of atherosclerosis-induced thrombosis, for the manufacture of a medicament for the prevention and treatment of hypercholesterolemia and endothelial dysfunction-induced ischemic damage and postischemic reperfusion injury, for the manufacture of a medicament for the prevention and treatment of hypercholesterolemia and endothelial dysfunction induced cardiac hypertrophy and cardiomyopathy and congestive heart failure (CHF), for the manufacture of a medicament for the prevention and treatment of hypercholesterolemia and endothelial dysfunction induced coronary artery spasm and myocardial infarction, for the manufacture of a medicament for the treatment of said conditions in combinations with antihypertensive agents, preferably with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists , A combination of an NHE inhibitor with a blood lipid level lowering agent, preferably with an HMG-CoA reductase inhibitor (for example, lovastatin or pravastatin), which induces a hypolipidemic effect and thereby enhances the hypolipidemic properties of the NHE inhibitor, proves to be a beneficial combination enhanced effect and reduced use of active ingredients.

Thus NHE inhibitors lead to an effective protection against endothelial damage of different origin. With this protection of the vessels against the syndrome of endothelial dysfunction, compounds of the formulas I, Ia, Ib, XVa, XVb and XVI and / or their pharmaceutically acceptable salts are valuable drugs for the prevention and treatment of coronary vascular spasms, peripheral vascular diseases, especially claudicatio intermittens , the atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy, and thrombotic disorders.

In addition, it has been found that NHE inhibitors are useful in the treatment of non-insulin-dependent diabetes (NIDDM), with insulin resistance being repressed. It may be beneficial to enhance the antidiabetic efficacy and potency of the compounds of the invention, these with a biguanide such as metformin, with an antidiabetic sulfonylurea such as glyburide, glimepiride, tolbutamide, etc., a glucosidase inhibitor, a PPAR agonist such as rosiglitazone, pioglitazone etc., with an insulin preparation different

Form of administration to combine with a DB4 inhibitor, with an insulin sensitizer or with meglitinide.

In addition to the acute antidiabetic effects, NHE inhibitors counteract the development of late diabetic complications and may therefore be used as medicaments for the prevention and treatment of late diabetic lesions such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and others as a result of diabetes Diseases are used. They can be advantageously combined with the antidiabetic medicines just described under NIDDM treatment. The combination with a favorable dosage form of insulin should be of particular importance.

NHE inhibitors show, in addition to the protective effects against acute ischemic events and the subsequent equally acute reperfusion events, also direct therapeutically useful effects against diseases and disorders of the entire mammalian organism, which are related to the phenomena of the chronic aging process and which are independent of acute deficient blood flow conditions and occur in normal, non-ischemic conditions. These pathological, age-related phenomena such as illness, infancy, and death, which have recently become accessible to treatment with NHE inhibitors, are major diseases and disorders caused by age-related changes of vital organs and their function and gaining in importance in the aging organism.

Disorders associated with age-related dysfunction, with age-related signs of organ deterioration, for example, are insufficient responsiveness and responsiveness of the blood vessels to contraction and relaxation reactions. This age-related decrease in vascular responsiveness to constrictive and relaxing stimuli, which is an essential process of the cardiovascular system, and thus of life and health, can be significantly abrogated by NHE inhibitors: an important function and measure of maintenance of the Vascular responsiveness is the blockade or retardation of age-related progressive endothelial dysfunction, which can be very significantly abrogated by NHE inhibitors. NHE inhibitors are thus outstandingly suitable for the treatment and prevention of age-related progressive endothelial dysfunction, in particular claudicatio intermittens.

An example of another parameter that characterizes the aging process is the decrease in the contractility of the heart and the decrease in the adaptation of the heart to a required pumping capacity of the heart. This diminished

Cardiac output as a result of the aging process is in most cases associated with dysfunction of the heart, which is inter alia caused by an incorporation of connective tissue into the heart tissue. This connective tissue embedding is characterized by an increase in heart weight, enlargement of the heart and limited cardiac function. It was surprising that such aging of the organ heart could be almost completely inhibited. NHE inhibitors are thus excellently suitable for the treatment and prevention of heart failure, congestive heart failure (CHF).

Proliferation inhibition can not only cure the already existing cancer, but also reduces the age-related incidence of cancer by NHE inhibitors and be significantly significantly delayed. Particularly noteworthy is the finding that age-related diseases of all organs and not just certain forms of cancer prevented or highly significantly delayed. NHE inhibitors are thus suitable for the treatment and in particular the prevention of age-related forms of cancer.

NHE inhibitors are associated with a highly significant delay in the onset of age-related disease in all organs examined, including the heart, blood vessels, liver, etc., as well as a highly significant retardation of senile cancer. Rather, surprisingly, there is also a prolongation of life to an extent that could not previously be achieved by any other drug group or by any natural products. This unique effect of the NHE inhibitors also makes it possible, in addition to the sole use of active substances in humans and animals, these NHE inhibitors with other gerontologically used active principles, measures, substances and

Natural products that are based on another mechanism of action. Such drug classes used in gerontological therapy are: in particular vitamins and antioxidant substances. Since there is a correlation between caloric stress and food intake and aging process, the combination can be done with dietary measures, for example, with appetite suppressants. Also, a combination with antihypertensive drugs, such as with ACE inhibitors, angiotensin receptor antagonists, diuretics, Ca ⁺ 2 antagonists, etc., or with metabolism-normalizing drugs, such as cholesterol, be thought. NHE inhibitors are thus outstandingly suitable for the prevention of age-related tissue changes and for prolonging life while maintaining a high quality of life.

The compounds of the present invention are potent inhibitors of the cellular sodium proton antiporter (Na / H exchanger), which in many diseases (essential hypertension, atherosclerosis, diabetes, etc.) is also increased in those cells which are readily accessible to measurements, such as in erythrocytes, Platelets or leukocytes. The compounds used in the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostic agents for the determination and differentiation of certain forms of hypertension, but also atherosclerosis, diabetes and diabetic late complications, proliferative diseases, etc.

Also claimed is a remedy for human, veterinary or phytoprotective use which, together with pharmaceutically acceptable excipients and adjuvants, contains an effective amount of one or more compounds of formulas XVa, XVb and XVI and / or their pharmaceutically acceptable salts, alone or in combination with other pharmacological agents or medicines. Medicaments which contain a compound of the formulas I, Ia, Ib, XVa, XVb and XVI and / or their pharmaceutically acceptable salts can be administered, for example, orally, parenterally, intravenously, rectally, percutaneously or by inhalation, with the preferred application depends on the particular appearance of the disease. The compounds of the formulas I, Ia, Ib, XVa, XVb and XVI can be used alone or together with pharmaceutical excipients, both in veterinary and in human medicine. The medicaments contain active compounds of the formulas I, Ia, Ib, XVa, XVb and XVI and / or their pharmaceutically acceptable salts, generally in an amount of 0.01 mg to 1 g per dosage unit.

Which excipients are suitable for the desired drug formulation is familiar to the person skilled in the art on the basis of his or her specialist knowledge / apart from solvents, gelling agents, suppository bases, tablet excipients, and others

Active substance carriers can be used, for example, as antioxidants, dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers or dyes.

For an oral application form, the active compounds are mixed with the appropriate additives, such as carriers, stabilizers or inert diluents and by the usual methods in the appropriate Dosage forms brought, such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions. As inert carriers, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch may be used. In this case, the preparation can be carried out both as dry granules and as moist granules. Suitable oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.

For subcutaneous, intramuscular or intravenous administration, the active compounds, if desired with the customary substances such as

Solubilizers, emulsifiers or other excipients in solution, suspension or emulsion brought. Examples of suitable solvents are: water, physiological saline solution or alcohols, for example ethanol, propanol, glycerol, but also sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.

Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of the formulas I, Ia, Ib, XVa, XVb and XVI and / or their pharmaceutically acceptable salts in a pharmaceutically acceptable solvent, such as in particular ethanol or water, or a mixture of such solvents. If desired, the formulation may also contain other pharmaceutical auxiliaries, such as surfactants, emulsifiers and stabilizers, as well as a propellant gas. Such a preparation usually contains the active ingredient in a concentration of about 0.1 to 10, in particular from about 0.3 to 3 wt .-%.

The dosage of the active ingredient of the formulas I, Ia, Ib, XVa, XVb and XVI to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; also the type and strength of the disease to be treated as well as the sex, age, weight and individual responsiveness of the mammal to be treated. On average, the daily dose of a compound of formulas I, Ia, Ib, XVa, XVb and XVI and / or their pharmaceutically acceptable salts in a patient weighing about 75 kg is at least 0.001 mg / kg, for example 0.01 mg / kg to at most 10 mg / kg ,. for example, 1 mg / kg body weight. In acute outbreaks of the disease, such as immediately after suffering a heart attack, even higher and above all more frequent dosages may be necessary, for example up to 4 single doses per day. In particular when administered iv, for example in an infarct patient in the intensive care unit can be necessary to 700 mg per day and the inventive ^'SEN compounds may be administered by infusion, for example up.

List of abbreviations:

DCC dicyclohexyl carbodiimide

DIP diisopropyl ether

TLC thin layer chromatography

DMF N, N-dimethylformamide

EE ethyl acetate eq. equivalent to

Et ₃ N triethylamine

Et ₂ 0 diethyl ether

EtOH ethanol h hour (s)

HEP n-heptane

HOAc acetic acid

KOtBu Potassium 2-methylpropan-2-olate

MeOH methanol min minute (s) mp melting point

MTB tert-butyl methyl ether

NMP 1 -methylpyrrolidin-2-one

Pd (OAc) ₂ palladium (II) acetate

RT room temperature Retention time tBu tert-butyl

THF tetrahydrofuran

TMEDA N.N.N'.N'-tetramethyl-ethane-1,2-diamine

The retention times (rt) given below refer to HPLC measurements with the following parameters:

Method A:

Stationary phase: Waters Symmetry C8 (5μ) 3.9x150mm Mobile phase: isocratic CH3CN / O.I% aqueous CF3CO2H 35:65; λ = 220 nm; 1 ml / min.

Method B:

Stationary phase: Waters Symmetry C8 (5μ) 3.9x150mm

Mobile phase: isocratic CH3CN / O.I% aqueous CF3CO2H 40:60; λ = 230 nm; 1 ml / min.

Method C:

Stationary phase: Waters Symmetry C8 (5μ) 3.9x150mm

Mobile phase: isocratic CH3CN / O.I% aqueous CF3CO2H 50:50; λ = 220 nm; 1 ml / min.

Example 1 a) N- (2,2,2-trifluoro-ethyl) -4-trifluoromethyl-benzamide

5.0 g (24 mmol) of 4-trifluoromethylbenzoyl chloride and 5.0 ml (36 mmol) of triethylamine were dissolved in 50 ml of CH 2 Cl 2 and 2.4 g (24 mmol) of 2,2,2-trifluoroethylamine were slowly added at RT dropwise. 4 h was stirred at RT, then the volatiles removed in vacuo. The residue was taken up in 100 ml of MTB and washed first with 30 ml of a saturated aqueous Na 2 CO 3 solution and then with 30 ml of a saturated aqueous NaHSO 4 solution. about

MgSO 4 was dried to obtain 6.1 g (94%) of a colorless resin which crystallized on standing; mp: 117 ° C.

Rf (DIP) = 0.50 MS (El): 271 (M + 1) ⁺

b) (R, S) -3-hydroxy-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydroisoindol-1-one

0.37 ml (2.4 mmol) TMEDA and 1.4 ml (2.3 mmol) of a 1.5 M solution of t-BuLi in n-pentane were dissolved at -75 ° C. in 2 ml THF (anhydrous) and at -75 ° C, a solution of 0.30 g (1, 1 mmol) of N- (2,2,2-trifluoro-ethyl) -4-trifluoromethyl-benzamide in 2 ml of THF was added dropwise. Stirred at -75 ° C for 3 h, then added dropwise 0.43 ml (5.5 mmol) of DMF and warmed to RT for 30 minutes. The reaction mixture was poured onto 100 ml of a saturated aqueous NaHCO 3 solution and 3 times with 30 ml

EE extracted. About MCJSO4 was dried and the solvent removed in vacuo. Chromatography on silica gel with DIP provided 80 mg of the (R, S) -3-hydroxy-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydro-isoindol-1-one besides 110 mg mixture with starting material. This mixture was re-separated by reversed-phase HPLC (see below for conditions) to give an additional 40 mg of (R, S) -3-hydroxy-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2, 3-dihydro-isoindol-1-one; Total yield 30%.

HPLC: gradient, running time 20 min

Eluent: 0.1% aqueous CF 3 CO 2 H, acetonitrile (Chromasolv); Flow: 30ml / min Column: Waters Xterra ™ MS C18 5μm, 30x100mm

Gradient:

0 - 2.5 min 10% acetonitrile 3.0 min 25% acetonitrile

14.0 min 75% acetonitrile

15.0 min 95% acetonitrile

17.5 min 10% acetonitrile

Rf (DIP) = 0.50 MS. (EI): 299 (M + 1) ⁺

c) (RS) - [3-Oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] -acetic acid ethyl ester

Under argon, (diethoxy-phosphoryl) -acetic acid ethyl ester (135 mg, 0.6 mmol) was dissolved in anhydrous dimethoxyethane (10 ml). 17.6 mg Nah (60% in oil) was added to this solution at RT and the mixture was stirred at RT for 10 min. Thereafter, a solution of (RS) -3-hydroxy-2- (2,2,2-trifluoroethyl) -5-trifluoromethyl-2,3-dihydroisoindol-1-one 120 mg (0.04 mmol) in anhydrous Dimethoxyethane (5 ml) was added and then stirred at reflux for 2 h. The reaction solution was allowed to cool, the

The reaction solution was then poured into 50 ml of 5% sodium bicarbonate solution, extracted twice with 20 ml of ethyl acetate each time, the organic phase was dried over MgSO 4, evaporated in vacuo and the residue was purified by chromatography on silica gel with DIP as eluent. 90 mg (61%) of (RS) - [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] were obtained. acetic acid ethyl ester as a colorless oil which crystallized from heptane as a beige solid. Rf (DIP) = 0.31 The NMR spectrum was identical to the material prepared in Example 4.

d) (R, S) -N- {2- [3-Oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-H-isoindol-1-yl] - acetyl-guanidine

The (RS) - [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] - acetic acid ethyl ester can as in Example 2g) can be reacted with guanidine.

Example 2 a) 2-nitro-4-trifluoromethylbenzoic acid

11.97 g of 4-trifluoromethylbenzoic acid (63 mmol) were slowly added portionwise to 48 ml of HNO3 (100%) at RT. The mixture was then heated at reflux for 1 h, then cooled to RT and poured onto about 600 g of ice. The mixture was stirred for 1 h, then the precipitate was filtered off and washed with 1 l of water. The filtrate was extracted with 300 ml CH 2 Cl 2, the organic phase was combined with the precipitate and dried over Na 2 SO 4. The solvent was removed in vacuo and the residue was recrystallized by dissolving in 1 liter of DIP at 68 ° C, adding 2 l HEP at this temperature and finally cooling the solution slowly to RT. The crystallized product was washed with 1 L HEP, dried in vacuo to give 7.1 g (48%), mp 136 ° C-138 ° C. b) 2-amino-4-trifluoromethylbenzoic acid

250 g of 2-nitro-4-trifluoromethyl-benzoic acid (1.06 mol) were dissolved in 1 L of EtOH and 7.5 g of Pd / C (5%) were added. The mixture was hydrogenated under 1-2.5 bar hydrogen pressure. During the hydrogen uptake, the temperature increased in the meantime from 10 ° C to 104 ° C. After 2 h, the hydrogen uptake had ended. The catalyst was then filtered off, the solvent removed in vacuo to give 215 g (99%) of a pale yellow solid, mp 174-176 ° C.

c) 2 - ((E) -2-ethoxycarbonylvinyl) -4-trifluoromethylbenzoic acid

520 mg NaNO 2 (7.6 mmol) were dissolved in 2 ml water and added to a solution of

1, 3 g of 2-amino-4-trifluoromethyl-benzoic acid (6.5 mmol) in 2.6 ml of a 48% aqueous HBF4 solution and 30 ml of ethanol were added dropwise at 0 ° C. Stirred at 0 ° C for 10 minutes, then warmed to RT. Another 0.3 ml of a 48% aqueous HBF4

Solution was added, then 30 ml of ethanol, 0.9 g of ethyl acrylate

(9.0 mmol) and 26.9 mg Pd (OAc) 2 (0.12 mmol). Subsequently, the mixture was stirred at 50-60 ° C for 1 h. The solvent was then removed in vacuo, the residue was taken up in 25 ml of EA and washed first with 25 ml of a 1 N aqueous HCl solution and then with 25 ml of a saturated aqueous NaCl solution. The organic phase was dried over Na 2 SO 4 and the solvent was removed in vacuo. The residue was suspended in 25 ml of heptane and the precipitated product was filtered off. Yield 1.3 g (69%) of a pale brownish solid. An analytical sample was purified by crystallization from heptane / ethyl acetate. The NMR spectrum was identical to the material prepared in Example 3a.

d) Ethyl (E) -3- [2- (2,2,2-trifluoro-ethylcarbamoyl) -5-trifluoromethyl-phenyl] -acrylate

1, 3 g of 2- (2-ethoxycarbonyl-vinyl) -4-trifluoromethyl-benzoic acid (4.5 mmol) and 453 mg of 2,2,2-trifluoro-ethylamine (4.5 mmol) were dissolved in 5 ml of DMF and 0.93 g DCC was added. The mixture was stirred at RT for 4 h. The urea by-product was removed by filtration and then the solvent was removed in vacuo. The residue was recrystallized from DIP to give 1.6 g (96%) of white crystals. The NMR spectrum was identical to the material prepared in Example 3b.

e) (RS) - [3-Oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl-acetic acid

2.2 g of ethyl (E) -3- [2- (2,2,2-trifluoro-ethylcarbamoyl) -5-trifluoromethyl-phenyl] -acrylate (5.9 mmol) were dissolved in 10 ml of methanol and 1, Add 5 ml of a 5 M aqueous NaOH solution (7.5 mmol). The mixture was stirred at RT for 18 h and then adjusted to pH = 7 with aqueous HCl solution. The solvents were removed in vacuo and the residue was suspended in 10 ml of water. This suspension was with a 2N aqueous HCl solution to pH = 2 and extracted 3 times with 10 ml of EA.

About Na 2 SO 4 was dried and the solvent was removed in vacuo. The residue was crystallized with diethyl ether / DIP, mp: 202-204 ° C.

Yield 1.8 g (89%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 3.07 (dd, Jι = 17 Hz, J ₂ = 6 Hz, 1 H), 3.23 (dd, J ^ 17 Hz,

J ₂ = 5 Hz, 1 H), 4.27 (m, 1 H), 4.58 (m, 1 H), -5.08 (t, J = 5 Hz, 1 H), 7.91 (d, J = 8 Hz, 1 ^'

H), 7.96 (d, J = 8Hz, 1H), 8.12 (s, 1H), 12.50 (bs, 1H) ppm.

. Combustion Analysis: C ₁₃ H ₉ F ₆ N0 ₃ (341.2): calcd C 45.76 H 2.66 N4.10; gef. C 45.71 H

2.43 N 4.11.

f) (RS) - [3-Oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] -acetic acid ethyl ester

2.6 ml of SOCl 2 (35 mmol) were dissolved in 20 ml of ethanol and 3.4 g of (R, S) - [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2 , 3-dihydro-1H-isoindol-1-yl] -acetic acid (10 mmol) at -10 ° C was added. The mixture was stirred at RT for 18 h and then the volatiles were removed in vacuo. The residue was chromatographed on silica gel with HEP / EA 3: 1. Yield 3.0 g (81%) of a colorless oil which crystallized from heptane as a beige solid. The NMR spectrum was identical to the material prepared in Example 4.

g) (RS) -N- {2- [3-Oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-H-isoindol-1-yl] -acetyl } guanidine

Guanidine hydrochloride (11.5 g, 120 mmol) was dissolved in NMP (45 ml) and KOtBu (11.2 g, 100 mmol) added with stirring, allowed to stir at RT for 1.5 h and the mixture filtered. The filtrate was added to a solution of (RS) - [3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] - ethyl acetate (7.38 g, 20 mmol) in NMP (12 ml) was added dropwise with stirring at RT and allowed to stir for a further 60 min at RT. Then, ice-water (270 ml) was added, adjusted to pH 7 with 2N HCl, added with ethyl acetate (60 ml), and then the pH was adjusted to 8-8.5 by addition of NaHCO ₃ solution. The mixture was stirred vigorously for 1 h at RT and the precipitate formed was filtered off with suction and washed with water. This gave 7.06 g (83%) of (R, S) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro- H-isoindol-1-yl] -acetyl} -guanidine, inclusion compound with 0.5 equivalents of ethyl acetate, as pale yellow crystals, mp.160-161 ° C with slow warming, evolution of ethyl acetate from about 90 ° C. Rf (ethyl acetate / methanol) = 0.45

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 2.54 (dd, Jι = 8 Hz, J ₂ = 16 Hz, 1 H), 3.09 (dd, J ^ 4 Hz, J ₂ = 16 Hz, 1 H ), 4.25 (m, 1H), 4.64 (m, 1H), 5.18 (m, 1H), 6.65 (bs, 2H), 7.75 (bs, 2H), 7.88 (d, J = 8Hz, 1H), 7.95 (d, J = 8Hz, 1H), 8.02 (s, 1H) ppm. . Cι ₄ H ₁₂ F ₆ N ₄ 0 ₂ × _^1/2 C ₄ H ₈ 0 ₂ (426.33): calcd C 45.08, H 3.78, N 13:14; gef. C 45.07, H 3.79, N 13.01.

Example 3 a) 2 - ((E) -2-ethoxycarbonylvinyl) -4-trifluoromethylbenzoic acid (variant of the example

2c)

To 339 g of 2-amino-4-trifluoromethylbenzoic acid (1.65 mol) in 6.8 l EtOH (anhydrous) was added at RT 658 ml of a 48-50% aqueous HBF4 solution. The temperature rose from 21 ° C to 26 ° C. Then, the mixture was cooled to 0 ° C and a solution of 125 g of NaNÜ2 in 500 ml of water was added dropwise for 17 minutes between 0 ° C and 5 ° C. The initially pale yellow solution initially became an orange-red suspension and finally a light yellow suspension. The course of the reaction was monitored by HPLC (method B; rt 2-amino-4-trifluoromethylbenzoic acid = 6.4 min, intermediate 2-carboxy-5-trifluoromethyl-benzenediazonium salt = 1, 1 min within 30 minutes When the reaction to give the 2-carboxy-5-trifluoromethyl-benzenediazonium salt was> 99% complete, 231 g of ethyl acrylate (2.31 mol), 11.1 g of Pd (OAc) 2 (49 mmol ) and 6.8 l of ethanol

added (anhydrous) and the reaction mixture heated to 49-51 ° C. In this case, a uniform, with increasing temperature nitrogen evolution was observed. The reaction was monitored by HPLC (Method B; rt 2 - ((E) -2-

Ethoxycarbonyl-vinyI) -4-trifluoromethyl-benzoic acid = 16.4 min). After 45 minutes, the conversion rate was over 99%. The mixture was then cooled to RT and the solvent removed in vacuo. The residue was taken up in 3 l of EA and filtered off. The filtrate was then washed 3 times with each 2.1 l of an aqueous HCl solution, then with 1 l of a saturated aqueous NaCl solution. Dry over Na 2 SO 4, remove the solvent in vacuo to give 449 g of a tan solid. Including an impurity (4-trifluoromethylbenzoic acid, 6.3%) and solvent residues (RE, 4%) gave a yield of 83%. An analytical sample was purified by crystallization from heptane / ethyl acetate. Mp: 132-133 ° C ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.36 (t, J = 7 Hz, 3 H), 4.31 (q, J = 7 Hz, 2 H), 6.41 (d, J = 16 Hz, 1 H), 7.72 (d, J = 8Hz, 1H), 7.86 (s, 1H), 8.21 (d, J = 8Hz, 1H), 8.51 (d, J = 16Hz, 1H), 8.5-9.5 (bs, 1H) ppm.

Combustion Analysis: C13H11 F3O4 (288.23): calc. C 54.17, H 3.85; gef. C 54.24, H 3.74.

b) Ethyl (E) -3- [2- (2,2,2-trifluoroethylcarbamoyl) -5-trifluoromethylphenyl] acrylate

315 g of oxalyl chloride (2.48 mol) were added at 24 ° C. to a mixture of 650 g of 2- ((E) -2-ethoxycarbonyl-vinyl) -4-trifluoromethyl-benzoic acid at a temperature between 15 and 18 ° C. (2, 25 mol), 33 ml DMF and 7.8 l CH 2 Cl 2 added. Gas evolution was observed during the addition. The mixture was stirred at RT for 1 h, then cooled to 5 ° C. and 285 g (2.81 mol) was added over a period of 27 min at a temperature between 5 ° C. and 10 ° C. Stirring was continued at 5 ° C. for 10 min, then 279 g of 2,2,2-trifluoro-ethylamine (2, 81 mol) was added over a period of 27 min at a temperature between 9 ° C. and 20 ° C. The mixture was stirred at RT for 10 min, during which a thick precipitate precipitated out and, to improve the stirrability of the mixture, an additional 1 l CH 2 Cl 2 was added Reaction was monitored by HPLC (method C; rt: 2 - ((E) -2-ethoxycarbonyl-vinyl) -4-trifluoromethyl-benzoic acid = 5.9 min; rt: (E) -3- [2- (2, 2,2,2-trifluoroethylcarbamoyl) -5-trifluoromethylphenyl] -acrylic acid ethyl ester = 13.2 min.) After stirring at RT for a further 50 min, the reaction was complete and then volatile constituents of the reaction mixture were removed in vacuo, the residue with 12 I EE and 3 times with 2.5 l of water, then 2 times with 2.5 l of a saturated aqueous NaHCO 3 solution and finally with 1, 5 I of a saturated heat washed NaCl solution. Dry over MgSO 4, remove the solvent in vacuo and obtain 802 g of (E) -3- [2- (2,2,2-) Trifluorethylcarbamoyl) -5-trifluoromethyl-phenyl] -acrylic acid ethyl ester as a brown solid. This crude substance was combined with the crude product of another batch (177 g) and dissolved in 3 l of EA at 60-70 ° C and added at this temperature 14 I HEP in 1 I portions. Then the mixture was heated to 80 ° C and stirred for 1, 5 h at this temperature. This mixture was then added to 5.6 l of 70 ° C warm HEP and the mixture was then cooled to RT with stirring for a period of 5 h. The product was then filtered, washed with 3 L of HEP, air dried to give 689 g of ethyl (E) -3- [2- (2,2,2-trifluoroethylcarbamoyl) -5-trifluoromethylphenyl] -acrylate ( 67%) as a light brown solid. Mp: 161, 5-160 ° C.

1 H NMR (400 MHz, CDCl 3): δ = 1.33 (t, J = 7 Hz, 3 H), 4.05 (m, 2 H), 4.26 (q, J = 7 Hz, 2

H), 6.19 (bs, 1 H), 6.46 (d, J = 16 Hz, 1 H), 7.63 (d, J = 8 Hz, 1 H), 7.68 (d, J = 8 Hz, 1 H),

7.87 (s, 1H), 7.90 (d, J = 16 Hz, 1H) ppm.

Combustion analysis: C15H13F6NO3 (369.27): calc. C 48.79, H 3.55, N 3.79; gef. C 48.93, H 3.51, N 3.92.

c) (R, S) -N- {2- [3-Oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-H-isoindol-1-yl] - acetyl} -guanidine

386 g of ethyl (E) -3- [2- (2,2,2-trifluoroethylcarbamoyl) -5-trifluoromethylphenyl] acrylate (1:05 mol) were suspended in 600 ml of DMF and kept at a temperature between 5 ° C and 15 ° C slowly added in portions 4.7 g KOtBu (42 mmol). Cyclization to isoindolone was monitored by TLC (HEP / EA = 2: 1, ethyl acrylate: Rf = 0.32, isoindolone: Rf = 0.41). After one hour, the implementation was completed. In the meantime, 587 g of KOtBu were suspended in 2.2 l of DMF and 600 g of guanidinium chloride were added at a temperature between 20 ° C and 25 ° C. The mixture was stirred at 25 ° C for 1 h and then the KCl was filtered off. The filtrate with the released guanidine was then added to the reaction mixture containing isoindolone and stirred at RT for 2 h. The conversion to acylguanidine was monitored by HPLC (method B, wavelength 230 nm and 254 nm, isolindolone: rt = 15.1 min, acylguanidine: rt = 2.9 min). Subsequently, the reaction mixture was poured onto 14 l of ice-water, adjusted to pH = 8.5-9.0 with aqueous HCl solution and extracted 4 times with 3 l of EA each time. Then it was washed 3 times with 3 l of a saturated aqueous NaCl solution, dried over Na 2 SO 4 and the solvent was removed in vacuo. This gave 329 g (82%) of a brown solid. The product was combined with 3 other batches of the same preparation process; Total amount 842 g. These 842 g (2.2 mol) were digested in 2 l of EA and 5 l of Et2O for 2 h at 30 ° C. Then the solid was filtered off, washed twice with 2 l Et2O and dried in vacuo. 693 g (82% recovery) of an almost white solid were obtained. The compound crystallized from 2-Prop ^'anol as an inclusion compound with 0.5 equivalent of 2-propanol.

The NMR spectrum was identical to the S enantiomer prepared in Example 5b.

Example 4

(RS) - (2- (2,2,2-trifluoroethyl) -3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) -acetic acid ethyl ester by one-pot reaction starting from 2 - (( E) -2-ethoxycarbonylvinyl) -4-trifluoromethylbenzoic acid

To a suspension of 2 - ((E) -2-ethoxycarbonyl-vinyl) -4-trifluoromethyl-benzoic acid (2.9 g, 10.1 mmol) in toluene (30 mL) at room temperature was SOCl 2 (1.98 g, 27.2 mmol) was added. It was stirred for 5 min. At room temperature and then heated to 105 ° C (bath temperature) within 30 min. Gas evolution started at around 70 ° C. It was stirred for 3 h at 105 ° C, then cooled Room temperature and suction filtered through a diatomaceous earth layer (2.5 x 0.5 cm), washed with toluene and the filtrate evaporated in vacuo. The acid chloride was obtained in the form of a reddish brown oil (3.34 g). 2,2,2-Trifluoroethylamine (1.2 g, 12.1 mmol) and triethylamine (2.58 g, 25.3 mmol) were dissolved in dichloromethane (15 ml) at 5 ° C, and under ice-cooling, the acid chloride was dissolved in dichloromethane (20 ml) was added dropwise so fast that the temperature was maintained between 5 ° C and 10 ° C. Then the ice bath was removed and the excess of trifluoroethylamine and a portion of the dichloromethane distilled off in a slight vacuum. The mixture was then refluxed for 10 h at reflux. After cooling, the mixture was diluted with dichloromethane (50 ml) and extracted by shaking twice with aqueous 2N HCl solution (50 ml each time), the combined organic phases were washed with water (100 ml), dried over Na 2 SO 4 and evaporated in vacuo. One obtained (RS) - (2- (2,2,2-

Trifluoroethyl) -3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) -acetic acid ethyl ester (3.51 g, 94%) as a dark brown oil, which was purified by crystallization from n-heptane , Mp: 54.5-55.5 ° C.

1 H-NMR (400 MHz, CDCl 3): δ = 1.15 (t, J = 7 Hz, 3 H), 2.85 (dd, J- = 6 Hz, J ₂ = 16 Hz, 1

H), 3.01 (dd, J = 5 Hz, J ₂ = 16 Hz), 1 H), 3.83 (m, 1 H), 4.12 (q, J = 7 Hz, 2 H), 4.73 (m, 1

H), 5.17 (t, J = 6Hz, 1H), 7.80 (m, 2H), 8.01 (d, J = 8Hz, 1H) ppm. Combustion analysis: C15H13F6NO3 (369.27): calc. C 48.79, H 3.55, N 3.79; gef. C 48.54, H 3.49, N 3.79.

Example 5 a) (S) -N- {2- [3-Oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] - acetylj-guanidine, O.O'-dibenzoyl-L-tartaric acid salt

(RS) -N- {2- [3-Oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] -acetyl} -guanidine (Inclusion compound with ethyl acetate, content 87.06% according to NMR, 44 g, 100 mmol) and 0,0'-dibenzoyl-L-tartaric acid (11, 2 g, 31 mmol) were as

Submitted solids and with stirring 2-propanol (500 ml) was added dropwise. At first, the solids completely dissolved, then a white precipitate precipitated. After 30 minutes, the mixture was heated to 70 ° C. This again resulted in an almost clear solution. This was allowed to cool to room temperature over 4 h and then stirred at this temperature overnight. Thereafter, the mixture was stirred for 4 h at 10 ° C and then filtered with suction. The residue was washed twice with 2-propanol (100 ml each time) and dried in air. This gave 28.05 g of (S) -N- {2- [3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl ] -acetyl} -guanidine, O.O'-dibenzoyl-L-tartaric acid salt (74% yield based on the (S) -enantiomer), enantiomeric purity 82% ee according to HPLC (Chiracel OD / 21, 250 x 4.6 mm, n-heptane / ethanol / methanol 50: 5: 2, 1 ml / min, 30 ° C) as colorless crystals. 20 g (14.6 mmol) of these crystals were initially charged and 2-propanol (400 ml) was added dropwise. The mixture was heated to 80 ° C with stirring and then allowed to cool slowly to room temperature. The mixture was stirred for a further 2 hours at this temperature and then filtered off with suction, the residue was washed twice with 2-propanol (50 ml each time) and dried in air. This gave 16.3 g (100% yield based on the (S) -enantiomer) of (S) -N- {2- [3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl -2,3-dihydro-1 H- isoindol-1-yl] -acetyl} -guanidine, OO ^{'Dibenzoyl-L-tartaric} acid salt as colorless crystals, mp: 192-193 ° C, enantiomeric purity> 97% ee by HPLC ( Conditions as above). Combustion analysis: C14H12F6N4O2 x ¹ / z C18H14O8 (561.43): calc. C 49.21, H 3.41, N 9.98; gef. C 49.17, H 3.30, N 9.97.

b) (S) -N- {2- [3-Oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl-acetyl-guanidine

(S) -N- {2- [3-Oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] -acetyl} -guanidine , 0,0 ^{'Dibenzoyl-L-tartaric} acid salt (113 mg, 0.20 mmol) was added (ml 1) in a mixture of water and (5 ml) was dissolved ethyl acetate and a solution of NaHCO 3 (50 mg) in water (7 , 5 ml) was added. The mixture was allowed to stand for 16 h

Stirred room temperature and then extracted three times with ethyl acetate (5 ml each). The combined organic phases were shaken once with a solution of NaHCO 3 (50 mg) in water (20 ml) and then with pure water (20 ml), dried with Na 2 SO 4 and evaporated in vacuo. This gave 75 mg (97%) of (S) -N- {2- [3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindole-1 yl] acetyl} guanidine. The product crystallized from 2-propanol as an inclusion compound with 0.5 equivalent of 2-propanol, mp: 80-82 ° C. The substance may also be recrystallized from ethyl acetate and crystallized with 0.5 equivalent of ethyl acetate, mp: 121, 5-122 ° C. Enantiomeric purity> 97% by HPLC (Chiracel OD / 21, 250 x 4.6 mm, n-heptane / 2-propanol 4: 1, 1 ml / min, 30 ° C).

¹ H-NMR (400 MHz, CDCl 3): δ = 2.54 (dd, J <| = 8 Hz, Ü 2 = 16 Hz, 1 H), 3.09 (dd, J <| = 4 Hz,

J ₂ = 16 Hz, 1H), 4.25 (m, 1H), 4.64 (m, 1H), 5.18 (m, 1H), 6.65 (bs, 2H), 7.75 (bs, 2

H), 7.88 (d, J = 8Hz, 1H), 7.95 (d, J = 8Hz, 1H), 8.02 (s, 1H) ppm. Combustion analysis (inclusion compound with 0.5 equivalent of 2-propanol): CH ₁₂ F 6 N 4 O 2 x Vz C ₃ H _δ O (412.32): calc. C 45.15, H 3.91, N 13.59; gef. C 45.23, H

4.27, N 13.10. Example 6

(RS) -N- {2- [3-Oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] -acetyl-guanidine Racemization of (R) -N- {2- [3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] -acetyl} guanidine

(R) -N- {2- [3-Oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] -acetyl-guanidine ( Inclusion compound with 0.5 equivalents of 2-propanol (M = 412.3), 43 g, 104 mmol, obtained by concentrating the mother liquor obtained in the precipitation of (S) -N- {2- [3-oxo-2- (2 , 2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] -acetyl} -guanidine, O.O'-dibenzoyl-L-tartaric acid salt in Example 5a), and Treatment with NaHCO 3 as described in Example 5b) was dissolved in 2-propanol (1.8 I) and at

At room temperature with stirring, a solution of KOH (85%, 660 mg, 10 mmol) in 2-propanol (400 ml) was added. The mixture was stirred at room temperature for 24 h and then acidified with glacial acetic acid (720 mg, 1, 5 ml) in vacuo at max. 40 ° C bath temperature and the residue partitioned between water (500 ml) and ethyl acetate (400 ml). The aqueous phase was extracted by shaking twice with ethyl acetate (300 ml each time). The combined organic phases were shaken with a solution of NaHCO 3 (10 g) in water (500 ml) and then again with pure water. The organic phase was dried with Na 2 SO 4 and concentrated in vacuo at max. 40 ° C bath temperature evaporated. 39.8 g of (RS) -N- {2- [3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl were obtained ] -acetyl} guanidine, content 87% by NMR, inclusion compound with 0.5 equivalent of ethyl acetate, as pale yellow crystals, yield 87%. Mp: 164-166 ° C with slow warming, escape of ethyl acetate from about 100 ° C. Enantiomeric ratio 49:51 according to HPLC (Chiracel OD / 21, 250 x 4.6 mm, n-heptane / 2-propanol 4: 1, 1mL / min, 30 ° C). Example 7

(S) - N - {2- [3-Oxo-2- (2,2,2-trifluoroethyl) -6-trifluoro-methyl-2,3-dihydro-1H-isoindol-1-yl] -acetyl} -guanidine Hydrogen fumarate hydrate

(S) -N- {2- [3-Oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] -acetyl-guanidine [ inclusion compound with 0.5 equivalent of 2-propanol, (M = 412.3), ^'110 g, 266 mmol] was dissolved in dimethoxyethane (2 I) and fumaric acid (0.5 M in dimethoxyethane / water 9: 1, 512 ml) added and the resulting clear solution was evaporated in vacuo. The residue was taken up in dichloromethane (2 L) and the mixture was again evaporated in vacuo. The residue was suspended in water (1.5 L), filtered off with suction at room temperature and dried in air at room temperature overnight. 125.9 g (95%) of (S) -N- {2- [3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindole-1 were obtained -yl] -acetyl} -guanidine Hydrogen fumarate hydrate as colorless crystals, m.p. 210 ° C.

Determination of NHE inhibition

The inhibitory concentration IC50 for NHE-1 inhibition was determined as follows:

IC50 for NHE-1 inhibition was determined in a FLIPR assay by measuring pHj recovery in transfected cell lines expressing human NHE-1.

The assay was performed in FLIPR (Fluorescent Imaging plate reader) with black-walled 96-well microtiter plates with clear bottom. The transfected cell lines expressing the various NHE subtypes (the parent cell line LAP-1 has no endogenous NHE activity as a consequence of mutagenesis and subsequent selection) were seeded the previous day at a density of -25,000 cells / well. The growth medium of the transfected cells (Iscove +10% fetal calf serum) additionally contained G418 as a selection antibiotic to ensure the presence of the transfected sequences.

The actual assay started with the removal of the growth medium and addition of 100 μl / well loading buffer (5 μM BCECF-AM [2 ', 7'-bis (carboxyethyl) -5- (and-6) -carboxyfluorescein, acetoxymethyl ester] in 20 mM NH 4 Cl, 115 mM choline chloride, 1 mM MgCl 2, 1 mM CaCl 2, 5 mM KCl, 20 mM HEPES, 5 mM glucose, pH 7.4 [adjusted with KOH]). The cells were then incubated at 37 ° C for 20 minutes. This incubation resulted in the loading of the cells with the fluorescent dye, the fluorescence intensity of which depends on pHi, and with NH4Cl, resulting in a slight

Alkalinization of the cells. The non-fluorescent dye precursor BCECF-AM is membrane permeable as ester. Intracellularly, the actual dye BCECF is liberated by esterases, which is not membrane permeable.

After this 20 minute incubation, the loading buffer containing NH4Cl and free BCECF-AM was washed three times in the cell washer (Tecan Columbus) with 400 μl wash buffer (133.8 mM choline chloride, 4.7 mM KCl, 1, 25 mM MgCl 2, 1, 25mM CaCl _2, 0.97mM K ₂ HP0 ₄ , 0.23mM KH ₂ PO ₄ , 5mM HEPES, 5mM glucose, pH 7.4 [adjusted with KOH]). The residual volume remaining in the wells was 90 μl (50-125 μl possible). This washing step removed the free BCECF-AM and resulted in an intracellular reaction as a result of the removal of the external NH4 ⁺ ions

Acidification (~ pH, 6.3 - 6.4).

Since the balance of intracellular NH4 ⁺ with NH3 and H ^{+ was} disturbed by the removal of the extracellular NH4 ^"1" and by the subsequent, instantaneous passage of NH3 through the cell membrane, the washing process resulted that intracellular H ⁺ remained behind, which was the cause of intracellular acidification. This can eventually lead to cell death if it lasts long enough. At this point, it was important that the washing buffer be sodium-free (<1 mM), as extracellular sodium ions cause instantaneous recovery of pHj by the

Activity of the cloned NHE isoforms would result.

It was also important that all buffers used (loading buffers, wash buffers,

Recovery buffers), since the presence of bicarbonate would result in the activation of interfering bicarbonate-dependent pHj regulatory systems contained in the parental LAP-1 cell line.

The microtiter plates with the acidified cells were then transferred to the FLIPR (up to 20 minutes after acidification). In FLIPR, the intracellular fluorescent dye was excited by 488 nm light generated by an argon laser, and the measurement parameters (laser power, exposure time and aperture of the FLIPR built-in CCD camera) were chosen to be the average Fluorescence signal per well was between 30,000 and 35,000 relative fluorescence units.

The actual measurement in the FLIPR started with software-controlled taking a picture every two seconds with the CCD camera. After ten seconds, recovery of intracellular pH was monitored by addition of 90 μl of recovery buffer (133.8 mM NaCl, 4.7 mM KCl, 1, 25 mM MgCl ₂ , 1, 25 mM CaCl ₂ , 0.97 mM K ₂ HP0 ₄ .

0.23 mM KH ₂ P0, 10 mM HEPES, 5 mM glucose; pH 7.4 [adjusted with NaOH]) by means of the 96-well pipettor installed in the FLIPR. As positive controls (100% NHE activity), wells to which pure recovery buffer was added, negative controls (0% NHE activity) were given washing buffer. In all other wells, recovery buffer containing the doubly concentrated test substance was added. The measurement in the FLIPR ended after 60 measuring points (two minutes). The raw data was exported to the ActivityBase program. This program first calculated the NHE activities for each substance concentration tested and from that the IC 50 values for the substances. Since the progression of pHj recovery was not linear throughout the experiment, but eventually declined due to decreasing NHE activity at higher pHj values, it was important for the

Evaluation of the measurement to select the part in which the fluorescence increase of the positive controls was linear.

Claims

claims

1. Process for the preparation of compounds of the formula I.

wherein R 1 and R 2 independently of one another denote hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 C atoms;

R3 is alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 C atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; and their salts; characterized in that

VII a) the amide of the formula IV is formylated and then cyclized to the compound of the formula VI, b) the compound of the formula VI is reacted with an alkoxycarbonylmethylenetriphenylphosphorane, with a 1-alkoxy-1-trimethylsiloxyethylene or with a trialkylphosphonoacetate to give the compound of the formula VII and c) the compound of the formula VII is reacted with guanidine to give the compound of the formula I, where in the compounds of the formulas IV, VI and VII, R1 to R3 are defined as in formula I and R5 is alkoxy having 1, 2, 3 or 4 C atoms is; and their salts.

2. A process for preparing compounds of the formula I according to claim 1 where R 1 and R 2, independently of one another, are hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl with 1, 2, 3 or 4 C atoms; R3 is alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 C atoms; ^' R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; and their salts; characterized in that

VII I

a) the compound of the formula II is reacted with the amine of the formula III to form the amide of the formula IV, b) the amide of the formula IV is formylated at the ortho position to the amide function to give the formylamide of the formula V, c) the formyl amid of formula V is cyclized to the compound of formula VI, d) the compound of formula VI is reacted with a Alkoxycarbonylmethylentriphenyl- phosphorane, with a 1-alkoxy-1-trimethylsiloxyethylen or with a trialkylphosphonoacetate to the compound of formula VII and e) the compound of formula VII is reacted with guanidine to the compound of formula I, wherein in the compounds of formulas II, III, IV, V, VI and VII

R1 to R3 are defined as in formula I,

R5 is alkoxy having 1, 2, 3 or 4 C atoms and X is Cl, Br, OH or alkoxy having 1, 2, 3 or 4 C atoms; and their salts

3. The method of claim 1 and / or 2, wherein the process steps are performed independently of each other continuously or discontinuously.

4. The method according to one or more of claims 1, 2 or 3, wherein the compound of formula I is defined as N- {2- [3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl] 2,3-dihydro-1H-isoindol-1-yl] -acetyl} -guanidine, and its pharmaceutically acceptable salts.

5. Process for the preparation of compounds of the formula I,

wherein R 1 and R 2 independently of one another denote hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 C atoms; R3 is AIk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 C atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; and their salts; characterized in that

a) the amine of formula IX is reacted with a diazonium salt with an acrylic acid alkyl ester to Zimtsäurederivat of formula XI, b) the compound of formula XI is reacted with the amine of formula III and with guanidine to the acylguanidine of formula I, wherein in the Compounds of formulas III, IX and XI R1 to R3 are defined as in formula I and R6 is alkoxy having 1, 2, 3 or 4 C atoms; and their salts. 6. A process for the preparation of compounds of formula I according to claim 5, wherein R1 and R2 independently of one another are hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl with 1 , 2, 3 or 4 C atoms; R3 is alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 C atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl with 3, 4, 5,

6 or 7 carbon atoms; and their salts; characterized in that

a) the nitro compound of the formula VIII is converted to the amine of the formula IX, b) the amine of the formula IX is converted to the diazonium salt of the formula X, c) the diazonium salt of the formula X with an acrylic acid alkyl ester for

D) the compound of formula XI is converted to the amide of formula XII and e) the compound of formula XII is converted to the acylguanidine of formula I, either by reacting the compound of formula XII in the presence of a base Isoindolone derivative of the formula XIII and then by reaction with guanidine with activation to the acylguanidine of the formula I (alternative A), or after formation of the isoindolone derivative of formula XIII in the presence of a base of the compound of formula XII by conversion of the compound of formula XIII into the ester of formula XIV and then by reaction with guanidine to the acylguanidine of formula I (alternative B), or by Reaction of the compound of formula XII in the presence of a strong base to the ester of formula XIV and then by reaction with guanidine to the acylguanidine of formula I (alternative C), or by direct reaction of the compound of formula XII with guanidine in the presence of a base with simultaneous success Guanylation and cyclization to the isoindolone of the formula I (alternative D), wherein in the compounds of the formulas VIII, IX, X, XI, XII, XIII and XIV R1 to R3 are defined as in formula I and R6 and R7 are independently alkoxy with 1 , 2, 3 or 4 carbon atoms; and their salts.

7. The method of claim 6, wherein in step e) the alternative D is used.

8. The method according to claim 6 and / or 7, wherein the method steps d) and e) are carried out in a one-pot process.

9. The method according to claim 5 and / or 6, wherein the process steps are performed independently of each other continuously or discontinuously.

10. The method according to one or more of claims 5 to 9, wherein the compound of formula I is defined as N- {2- [3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2, 3-dihydro-1H-isoindol-1-yl] -acetyl} -guanidine, and its pharmaceutically acceptable salts.

11. Compounds of the formula XII

wherein R 1 and R 2 independently of one another denote hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 C atoms; R3 is alk-R4 or trifluoromethyl; Alk alkyl having 1, 2, 3 or 4 C atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; R6 alkoxy having 1, 2, 3 or 4 carbon atoms; and their salts.

12. Compounds of formula XII according to claim 11 for use as synthesis intermediates.

13. A process for the isolation of compounds of formula Ia and Ib

where mean R 1 and R 2 independently of one another are hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 C atoms; R3 is alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 C atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; and their salts; characterized in that

la Ib a) the compound of formula I to salts of a 2,3-O-acylated D- or L-tartaric acid reacted and obtained by crystallization, the two salts of the formulas XVa and XVb separately, and b) the free bases of the formulas la or Ib are liberated from the two salts of formulas XVa and XVb, respectively,

Where R1 to R3 are defined in the compounds of the formulas I, XVa and XVb as in the formulas Ia and Ib R * means

R 8 is alkyl having 1, 2, 3, 4, 5 or 6 C atoms or phenyl which is unsubstituted or substituted by 1, 2 or 3 substituents from the group F, Cl, Br, I, alkyl having 1, 2, 3 or 4 C atoms or alkoxy having 1, 2, 3 or 4 C atoms.

14. The method of claim 13, wherein the undesired enantiomer of the formulas Ia or Ib is racemized again.

15. The method according to claim 13 and / or 14, wherein the compounds of the formulas la and Ib (R) -N- {2- [3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2 , 3-dihydro-1H-isoindol-1-yl] -acetyl} -guanidine and (S) -N- {2- [3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl- 2,3-dihydro-1H-isoindol-1-yl] -acetyl} -guanidine.

16. Compounds of the formula XVa and / or XVb

wherein R 1 and R 2 independently of one another denote hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 C atoms; R3 is alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 C atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 C atoms; R ⁷

R 8 is alkyl having 1, 2, 3, 4, 5 or 6 C atoms or phenyl which is unsubstituted or substituted by 1, 2 or 3 substituents from the group F, Cl, Br, I, alkyl having 1, 2, 3 or 4 C atoms or alkoxy having 1, 2, 3 or 4 C atoms.

17. (S) -N- {2- [3-Oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] -acetyl} -guanidine hydrogen fumarate hydrate of formula XVI.

18. A compound of the formulas XVa or XVb according to claim 16 or the formula XVI according to claim 17 for use as a medicament.

19. Use of a compound of formulas XVa or XVb according to claim 16 or of formula XVI according to claim 17, alone or in combination with others

Medicaments or active ingredients for the manufacture of a medicament for the treatment or prophylaxis of acute or chronic damage, diseases or indirect sequelae of organs and tissues caused by ischemia or by Reperfusion events, for the treatment or prophylaxis of arrhythmias, life-threatening ventricular fibrillation of the heart, heart attack, angina pectoris, for the treatment or prophylaxis of ischemic conditions of the heart, ischemic conditions of the peripheral and central nervous system or stroke or ischemic conditions peripheral organs and tissues, for the treatment or prophylaxis of shock conditions, of diseases in which cell proliferation is a primary or secondary cause of cancer, metastasis, prostatic hypertrophy or prostate hyperplasia, atherosclerosis or disorders of lipid metabolism , hypertension, essential hypertension, diseases of the

Central nervous system disorders, CNS over-excitability disorders, epilepsy or centrally-induced seizures, central nervous system disorders, particularly anxiety, depression or psychosis, for the treatment or prophylaxis of non insulin dependent diabetes mellitus (NIDDM) or diabetic late damage, thrombosis of disorders due to endothelial dysfunction, of claudicatio intermittens, for the treatment or prophylaxis of fibrotic disorders of internal organs, fibrotic disorders of the liver, fibrotic kidney diseases, fibrotic disorders of vessels and fibrotic diseases of the heart, for the treatment or prophylaxis of heart failure or congestive heart failure, acute or chronic iriflammatory diseases, diseases caused by protozoa, malaria and chickencoccidiosis and for use in surgical operations and organ transplants, to Kon Serving and storage of: ^• surgical grafts, bypass surgery, cardiac arrest relapse, prevention of age-related tissue alteration, manufacture of an anti-aging drug or prolongation of life, treatment and reduction of cardiotoxic effects in thyrotoxicosis or for the preparation of a diagnostic agent.

A human, veterinary and / or phytoprotective application remedy comprising an effective amount of a compound of formulas XVa or XVb of claim 16 together with pharmaceutically acceptable carriers and adjuncts.

A human, veterinary or phytoprotective use remedy containing an effective amount of a compound of formulas XVa or XVb of claim 16 together with pharmaceutically acceptable carriers and adjuvants in combination with other pharmacologically active agents or medicaments.

22. Remedies for human, veterinary and / or phytoprotective use containing an effective amount of the compound of formula XVI according to claim 17 together with pharmaceutically acceptable carriers and additives.

23. Remedies for human, veterinary or phytoprotective use _. containing an effective amount of the compound of the formula XVI according to claim 17 together with pharmaceutically acceptable excipients and additives in combination with other pharmacologically active substances or medicaments.